The basic scientific goals of Project 1 and the central goals of the Program Project are to (1) understand the circuitry in humans that underlies cocaine-induced euphoria, withdrawal dysphoria, and cocaine- conditioned craving, and (2) to investigate differences in regional brain activation by cocaine in nondependent versus dependent users. In Project 1, we test the hypotheses that: the neural substrates of cocaine-induced euphoria and early post-cocaine dysphoria can be specifically imaged by alterations in fMRI signal; that cocaine dependence will alter the way in which subsequent cocaine administration activates the brain; and that the functional anatomy of human cocaine craving will reflect activation of a subset of the regions activated directly by cocaine. We have chosen to use fMRI technology to study the human neurobiology of cocaine action because subjects will not be exposed to ionizing radiation or injected contrast material. This makes longitudinal studies feasible; moreover fMRI offers the spatial and temporal resolution needed to study the neural correlates of rapidly changing human subjective states.